FDA Grants Avelumab/Axitinib Combo Priority Review for RCC

The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) for the combination of avelumab (Bavencio) and axitinib (Inlyta) as a treatment for patients with advanced renal cell carcinoma (RCC).1

The decision is based on findings from the pivotal phase III JAVELIN Renal 101 trial, which were presented at the 2018 ESMO Congress. Results showed that the combination significantly improved progression-free survival (PFS) and doubled the objective response rates (ORR) when compared with sunitinib (Sutent) in patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.2

The agency is expected to decide on the application in June 2019, according to Pfizer, the developer of both agents.

“The combination of Bavencio with Inlyta builds on Pfizer’s significant heritage in advancing standards of care for patients with advanced RCC and has the potential to make a meaningful impact for the lives of patients,” Chris Boshoff, MD, PhD, chief development officer, Oncology, Pfizer Global Product Development, said in a press release. “We look forward to working with the FDA to bring this potential new treatment option to patients as quickly as possible.”

The rationale for combining these agents is that avelumab stimulates the immune system while axitinib inhibits tumor neoangiogenesis by preventing VEGF activity. Preclinical data have shown that combining this class of agents is effective, as their mechanisms of action complement each other. Axitinib is currently FDA approved as a second-line therapy for patients with advanced RCC.

In the JAVELIN Renal 101 trial, 886 patients with advanced or metastatic RCC were randomized 1:1 to receive 10 mg/kg of avelumab intravenously every 2 weeks plus 5 mg of oral axitinib twice daily in 6-week cycles or 50 mg of oral sunitinib once daily for a 4-weeks-on/2-weeks-off schedule. Patients with all MSKCC/Motzer Criteria with good- (21%), intermediate- (62%), and poor-risk disease (16%) were included.

The overall population included 560 (63.2%) PD-L1–positive patients. In the PD-L1–positive group, 270 patients received the combination and 290 patients were treated with sunitinib. In the overall group, 442 patients were treated with the combination while 444 received sunitinib. The primary endpoints were PFS by blinded independent central review and overall survival (OS) in the PD-L1–positive group; secondary endpoints were PFS and OS in the overall population irrespective of PD-L1 status, ORR, and safety.

Findings showed that, in the PD-L1–positive population, the median PFS was 13.8 months (95% CI, 11.1-NE) with avelumab/axitinib compared with 7.2 months (95% CI, 5.7-9.7) with sunitinib, leading to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95%, 0.475-0.790; P <.0001). The ORR with the combination was 55.2% (95% CI, 49.0-61.2), which included 4 complete responses (CRs) and 51 partial responses (PRs); the ORR with sunitinib was 25.5% (95% CI, 20.6- 30.9). Twenty-seven patients in the combination arm had stable disease (SD) and 11 had progressive disease (PD).

In the PD-L1–positive and overall population arms, 73% and 70% of patients remained on avelumab/axitinib treatment, respectively, versus 65% and 71% of those on sunitinib. Median duration of response was not yet reached in either treatment arm in either population. Additionally, OS data are not yet mature.

Regarding safety, the immunotherapy/TKI regimen was found to be favorable. Fifty-one (4%) patients on the combination arm and 48 (7%) patients on the sunitinib arm experienced grade 3/4 treatment-related adverse events (TRAEs), the most common being diarrhea (5% vs 3%). All-grade TRAEs were similar between arms. Four percent of TRAEs led to avelumab/axitinib discontinuation versus 8% with sunitinib; 1 patient on avelumab/axitinib died due to TRAEs.

Grade ≥3 TRAEs were reported in 71.2% of patients in the combination arm versus 71.5% of patients in the sunitinib arm, and led to treatment discontinuations in 22.8% versus 13.4%, respectively.

The priority review designation follows a breakthrough therapy designation for the combination, which the agency granted in December 2017. The breakthrough status was based on data from the phase Ib JAVELIN Renal 100 trial, which showed that frontline avelumab/axitinib led to a 58.2% response rate in patients with advanced RCC.3 Moreover, the CR rate was 5.5%, the PR rate was 52.7%, and the disease control rate was 78.2%.